We propose to adapt a very successful approach to "permanent" cardiac allografts in rats to dogs to solve problems presented by larger, non-inbred animals like humans. Lethally irradiated rats grafted with allogeneic hearts and repopulated with syngeneic marrow, thymus, spleen and lymph node cells after a two-day delay permanently accepted the hearts and were tolerant to donor cardiac tissue. If the cells were infused on the day of irradiation and heart transplantation, the grafts were promptly rejected. We concluded that the irradiated host had eliminated intragraft hemopoietic cells responsible for the grafts' immunogenicity. We propose to test an alternate hypothesis regarding accessory cell function to explain the tolerance phenomenon. To reproduce these results in dogs, we propose to remove prospective recipient bone marrow and lymphoid cells and store them cryogenically. The donor-host degree of incompatibility will be estimated by performing mixed lymphocyte cultures. The hosts will be lethally irradiated and grafted with allogeneic hearts heterotopically in the neck on the same day. Autologous hemopoietic cells will be infused either on the same day or two days later. Survival times of the grafts will be determined by daily testing for electrical and pulsatile activity. If this approach is successful, orthotopic transplants will be attempted and the clinical application of this model will be feasible. Concurrent experiments in rodents will investigate the mechanism of tolerance or enhancement and will develop information for improved protocols on the dog model.